Changing the metal atom within a metallocene nucleoside analogue from iron to ruthenium results in a five-fold reduction in biological activity in a pancreatic cancer cell line.

Patients feel more vulnerable when accessing community mental health programs for the first time or after being discharged from psychiatric inpatient units. Long wait times for follow-up appointments, shortage of mental health professionals, lack of service integration, and scarcity of tailored support can weaken their connection to the health care system. As a result, patients can present low adherence, dissatisfaction with treatment, and recurrent hospitalizations. Finding solutions to avoid unnecessary high-cost services and providing tailored and cost-effective mental health interventions may reduce the health system burden and augment patient support. We propose implementing an add-on, supportive text messaging service (Text4Support), developed using cognitive–behavioural therapy (CBT) principles to augment mental health support for patients attending to or being discharged from psychiatric care in Nova Scotia, Canada. This randomized controlled trial aims to investigate the effectiveness of Text4Support in improving mental health outcomes and overall mental well-being compared with usual care. We also will examine the intervention’s impact on health services utilization and patient satisfaction. The results from this study will provide evidence on stepped and technology-based mental health care, which will contribute to generating new knowledge about mental health innovations in various clinical contexts, which is not only helpful for the local context but to other jurisdictions in Canada and abroad that are seeking to improve their health care.

We describe the generation and characterization of camelid single-domain antibodies (nanobodies) raised against tumor suppressor protein p16INK4a (p16). p16 plays a critical role in the cell cycle by inhibiting cyclin-dependent kinases CDK4 and CDK6, and it is inactivated in sporadic and familial cancers. The majority of the p16 missense mutations cause loss of function by destabilizing the protein structure. We show that the nanobodies bind p16 with nanomolar affinities and restore the stability of a range of different cancer-associated p16 mutations located at sites throughout the protein. The nanobodies also bind and stabilize p16 in a cellular setting. The crystal structure of a nanobody-p16 complex reveals that the nanobody binds to the opposite face of p16 to the CDK-binding interface permitting formation of a ternary complex. These findings indicate that nanobodies could be used as pharmacological chaperones to determine the consequences of restoring the function of p16 in the cell.

Activated Cdc42-associated kinase (ACK), a non-receptor tyrosine kinase, is an effector for the small GTPase Cdc42. ACK is emerging as an important component of the cancer landscape and thus, a promising target for the treatment of many malignancies. ACK is also being increasingly recognized as a potentially influential player in the regulation of protein homoeostasis. The delicate equilibrium between protein synthesis and protein degradation is crucial for healthy cell function and dysregulation of protein homoeostasis is a common occurrence in human disease. Here, we review the molecular mechanisms by which ACK regulates the stability of diverse cellular proteins (e.g. EGFR, p27, p53, p85 isoforms and RhoGDI-3), some of which rely on the kinase activity of ACK while others, interestingly, do not. Ultimately, further research will be required to bridge our knowledge gaps and determine if ACK regulates the stability of further cellular proteins but collectively, such mechanistic interrogation would contribute to determining whether ACK is a promising target for anti-cancer therapy. In therapeutics, proteasome inhibitors are an efficacious but problematic class of drugs. Targeting other modulators of proteostasis, like ACK, could open novel avenues for intervention.

Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.